delta3,5-pregnadiene derivatives



United States Patent Q 3,099,656 A -PREGNADIENE DERIVATIVES John A. Zderic, Palo Alto, Calif., Otto Halpern, Mexico City, Mexico, and Jose Iriarte, Zurich, Switzerland, assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Feb. 26, 1962, Ser. No. 175,810 16 Claims. (Cl. 269-23955) The present invention relates to novel cyclopentanophenanthrene derivatives and to a process tor the production thereof.

More particularly the present invention relates to novel 4-methyl-A apregnadiene derivatives.

The novel compounds of the present invention which are progestational agents with anti-estrogenic, antigonadotropic and anti-ovulatory properties are represented by the following formula:

In the above formula Y represents hydrogen or fluorine; R represents hydrogen or methyl; R represents hydroxyl or a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; R represents hydrogen, a-methyl, rnethyl, u-hydroxy or a-acyloxy; in addition R and R together may represent the group:

wherein P may be a lower allcyl group and Q represents a lower alkyl, or an aryl or aralkyl group, each containing up to 8 carbon atoms.

The acyloxy groups are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, fbenzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and p-chloropropionate.

The novel compounds of the present invention are prepared by the process exemplified by the following equa tion:

CHzY

CIH1Y 0 0 SW R.

CH3 CH8 3,099,656 Patented July 30, 1963 (i'lHzY (iJHzY C=O CHOH I. 4 4

MR5 MR In the above formulas Y and R have the same meaning as previously set forth; K may be a hydrocarbon carboxylic acy-loxy group of less than 12 carbon atoms; R represents hydrogen, a-methyl, fi-met-hyl or u-acyloxy; in addition R and R together may represent the group wherein P and Q have the same meaning as hereinbefore described.

In practicing the process outlined above, the starting compound which is a 4-methyl-A pregnene-3,ZO-dione derivative (I) is reduced with a double metal hydride, preferably sodium borohydride to give the cor-responding 35,203-dio1 and the Boa-isomer thereof (II). Reaction of this mixture in an acid medium, preferably 50% acetic acid, at steam bath temperature, for a period of time of the order of one hour, affords the corresponding 4- methyl-A -pregnadien-ZOfi-ol ('I'II). Oxidation of this latter compound, preferably with chromium trioxide in pyridine yields the corresponding 4-methyl-A -pregnadien-ZO-one (IV).

The compounds obtained by the above described procedures, which have a 17a-acyloxy group present in the molecule, yields the corresponding 17u-free hydroxyl derivative by conventional saponification, preferably with an alkali metal hydroxide.

The final compounds of the present invention having a ketonide at the 16,17-positions produce the 1606,1704 diols by hydrolysis with a strong acid, preferably formic acid;

The free alcohols thus obtained, are conventionally acylated with an excess of an acylating agent, as for example an anhydride derived from a hydrocarbon carboxylic acid of the type described hereinbefore in the presence of p-toluenesnlfonic acid, thus affording correspondingly the 17oz-monoacylates or the ;,17a-diacylates. The latter compounds, upon selective saponification in a mild alkaline medium yields the corresponding 16a-hydroxy-17a-acyloxy derivative which by further acylation gives the respective 16,17 diesters with the same or different ester groups.

Alternatively, conventional acylation of the 1604,17- diol in the absence of p toluenesulfonic acid yields the corresponding 16a-acyloxy-17a-hydroxy compound which upon further acylation in the presence of p-toluenesulfonic acid with the same or a difierent acylation agent gives the corresponding 16,17-diester with the same or ditferen-t ester groups.

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

PREPARATION 1 Progesterone was converted into a mixture of two isomeric ZO-enol acetates of the enolactone of 5,20-diketo- 3,5-secoA-nor-pregnan-3-carboxylic acid by the method of Fujimoto and 'Prager, J. Am. Chem. Soc. 75, 3260 Starting Compounds Products 4 methyl-l9-nor-progesterone.

4-methy1-17a-aceterry-progesterone.

4, lfia-dimethyl-progesterone.

4, IGB-dimethyl-progesterone.

4, lfia-dimethyl-lh-acetoxy progesterone.

4-methy1-21-fluoro-17a-acetoxy progesterone.

4-methyl-16a, 17a-dihydroxy- 19-nor-progesterone 17a-acetoxy-progesterone lfia-methyl-progesterone- IGB-methyl-progestcrone 1fia-methyl-lhacetoxy-proges- 16a, 17a-dihydroxy-progesteroneacetomde. progestorone-acetonide. 16, 17a-dihydroxy-progesterone- 4-methyl-16a- 17a-dihydroxyacetophenonidc. progesterone aeetophenonide.

PREPARATION 2 A culture of Streptomyces roseochromogenus ATCC 3347 was prepared in an inclined agar medium containing 1% of glucose and 1% of yeast extract. 1 cc. of a suspension of this culture was then used to innoculate each one of a series of 250 cc. flasks containing 50 cc. of a sterilized aqueous medium of 2% peptone and 5% corn syrup, the mixtures were then incubated in a shaking machine at 28 C. under aereation for a period of 24-48 hours. There was thus obtained a vegetating growing culture of Streptomyces roseochromogenus which was used for the subsequent incubation of the steroid.

10 mg. of 19-nor-A -pregnen-3p-ol-20-one-acetate (obtained by conventional acetylation of the free 3B-alcohol, prepared according to our copending Patent application Ser. No. 164,626, filed January 5, 1962) were added to each 50 cc. of the vegetating culture of Streptomyces raseochromagenus, obtained as described above. The mixture was stirred for 48-72 hours with aeration and then, extracted several times with methylene dichloride. The extract was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure.

The residue was purified by chromatography on silica gel thus giving l9-nor-n -pregnene-3fi,16a-dio1-20-one-3- acetate.

A solution of 8 g. of the latter steroid in 100 cc. of

chloroform containing a few drops of pyridine was cooled to C. and slowly treated under stirring with a cooled solution of chlorine in chloroform containing 1.05 molar equivalents of chlorine. The mixture was allowed to reach room temperature, the excess of chlorine was removed by flushing with dry air and the solution was washed with aqueous sodium bicarbonate solution and subsequently with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from methanol-benzene afforded 5a,6,8-dichlorol9rnor-pregnane-3B,l6o=-diol-20-one3-acetate. A solution of 5 g. of the latter 5a,6fi-dichloro compound in 25 cc. of pyridine was cooled to 0 C. Under stirring there was added 1.3 g. of tosyl chloride, the mixture was kept for 16 hours at 0 C., diluted with 100 cc. of chloroform, washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and again with water, dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. Thus there was obtained the crude 5a,6 3-dichloro-19-nor-pregnane3fl,16adiol-20-one-3-acetate-16-tosylate.

The total crude compound was kept at 50 C. with 5 g. of anhydrous sodium acetate and 160 cc. of ethanol dur-' ing 2.5 hours. Chloroform and water were added. The aqueous layer was extracted several times with chloroform and the combined organic extracts were washed with concentrated sodium bicarbonate solution, then with water, dried over sodium sulfate and evaporated to dryness. Chromatography and recrystallization of the solid fractions from acetone-hexane afiorded 5a,6fl-dichloro-19- nor-A -pregnen-3fi-ol-20-one-acetate.

50 cc. of dioxane containing 3 g. of the latter steroid and 3.46 cc. of pyridine were allowed to stand at room temperature for 6 days with 2.0 g. of osmium tetroxide. The mixture was then saturated with hydrogen sulfide and filtered through a pad of filter aid. The resultant colored filtrate was evaporated to dryness and taken up in 50 ml. of methanol. By stirring for 20 minutes with 10 g. of neutral alumina and 2 g. of decolorizing carbon and then filtering, the solution was almost completely decolorized and gave upon evaporation to dryness the crude material which was purified by chromatography on fiorisil. Recrystallization of the solid fractions from acetone-ether gave 5u,6;3-dichloro-19-nor-pregnane-3fl,l6a,17a-triol-20- one-3-acetate.

To 120 cc. of acetone containing 1 g. of the last named triol were added 30 drops of 78% perchloric acid. After 1 hour at room temperature 30 drops of pyridine were added and the resulting solution was evaporated to dryness under reduced pressure. 30 cc. of water were added to the residue and it was then extracted several times with 80 cc. of ethyl acetate. The combined extracts were washed to neutrality with water, dried over sodium sulfate and evaporated to dryness. The residue =upon trituration with methanol gave a crude 16,17-acetonide. Recrystallizations from the same solvent furnished 16oz, 17a-isopropylidenedioxy-5a,6fi-dichloro-l9-nor pregnan- 3p-ol-20-one-acetate.

A suspension of 1 g. of the latter steroid in 60 cc. of methanol was treated with a solution of 1 g. of potassium carbonate in 6 cc. of water; the mixture was boiled under reflux for 1 hour and then cooled in ice and diluted with water. The formed precipitate was collected and recrystallized from acetone hexane to yield l6a,17aisopropylidenedioxy-Sa,6B-dichloro-19-nor-pregnan-3B-ol- 20-one.

To a solution of l g. of the latter 5a,6,8-dichloro compound in 200 cc. of acetone, at room temperature and under a nitrogen atmosphere, there were added, 60 cc. of freshly prepared chrornous chloride solution. After 5 minutes the acetone was removed under reduced pressure, water was added and the precipitate filtered off and dried. Recrystallization from acetone-hexane yielded 16oz,17a-isopr0pylidenedioxy 19 nor-M-pregnen 35-01- 320-one.

A solution of 1 g. of the latter steroid in 80 cc. of toluene and 20 cc. of cyclohexanone was dried by distilling off 10 cc. of the solvent. A solution of 1 g. of aluminum isopropoxide dissolved in 7 cc. of anhydrous toluene was then added and the mixture was refluxed for 45 minutes; 4 cc. of acetic acid were added and the solvents removed by steam distillation. The product was extracted several times with ethyl acetate and the organic extracts washed with 5% hydrochloric acid solution, water, 10% sodium carbonate solution and water until neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetonehexane afiorded 16a,17a-isopropylidenedioxy-19-nor-A -pregnene- 3,20-dione, which upon treatment in accordance with preparation 1, yielded 4-methyl-16a,17a-isopropylidenedioxy-l9-nor-A -pregnene-3,20-dione.

PREPARATION 3 A mixture of 6.6 g. of 19-nor-A -pregnen-313-01-20-oneacetate 27 g. of p-toluenesulfonic acid and 300 cc. of acetic anhydride was submitted to a slow distillation; during 5 hours. The residue was cooled and poured into ice water. The product was then extracted with ether, the extract washed successively with an aqueous solution of sodium carbonate and water to neutral, dried and evaporated to dryness. The residue consisted of l9-nor- A -pregnadiene-3fl,20 3-diol diacetate which was utilized in the following step without purification.

6 g. of this crude diacetate were treated with 480 cc. of a 1.2 molar solution of per-benzoic acid in benzene (2.2 molar equivalents), at room temperature and in the dark, for hours. Water was then added, the organic layer separated, washed with an aqueous solution of sodium bicarbonate, then with water, dried with anhydrous sodium sulfate and evaporated to dryness. The residue consisted of the crude 5oz,6oz;17ec,20u-l)iS-OXid0 19-nor-ipregnane3fl,2OB-diol diacetate.

This crude oxido compound was treated with 500 cc. of 1% methanolic solution of potassiumhydroxide at room temperature for 1 hour, the mixture was neutralized by addition of acetic acid, concentrated to small volume under reduced pressure, the product was precipitated by addition of ice water, filtered oif, washed with water, dried and recrystallized from -acetone-rnethanol, thus yielding 5a,6a-oxido-l9-norepregnane-3fi,17a-diol-20-one- S-acetate.

To 5 -g. of the latter steroid in 80 cc. of glacial acetic acid, there was added a mixture of 6 g. of sodium iodide, 1.6 g. of sodium acetate, 320 mg. of zinc and 2 drops of water. While cooling in an ice bath and stirring, there were added to the resulting mixture, 800 mg. of zinc dust in small portions. The stirring was continued for 6 hours and the temperature allowed to attain C.

The reaction mixture was filtered and the filtrate diluted with ice water, alkalized with sodium bicarbonate and extracted with ethyl acetate. The extract was washed to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane yielded 19-nor-A -pregnene-35, l7a-diol20-one-3=acetate.

To a solution of 5 g. of the latter steroid in 100 cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonic acid and 10 cc. of acetic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to effect hydrolysis of the excess anhydride. 'I'he benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from etherhexane produced 19-nor-A -pregnene-3B,17e-diol-20-one diacetate.

A suspension of l g. of the last named compound, in 60 cc. of methanol was treated with a solution of 1 g. of potassium carbonate in 6 cc. of water; the mixture was boiled under reflux for 1 hour and then cooled in ice and diluted with water. The formed precipitate was collected and recrystallized from acetone-hexane to yield 17u-acetoxy-19-nor-A -pregnen-3,8-ol-20aone.

The latter steroid was treated by the Oppenauer procedure, as described in Preparation 2, thus giving 17aacetoxy-19-nor-A -pregnen-3,ZO-dione.

The last named ketone, was treated in accordance with Preparation 1, thus yielding 4-methyl-l7u-acetoxy-l9-nor- A -pregnen-3,20-dione.

PREPARATION 4 To a mixture of 1 g. of 5u,6fi-dichloro-19-ncr-A pregnen-3fl-ol-20-one acetate, 1 g. of cuprous chloride and cc. of anhydrous tetrahydrofuran was added, while stirring and cooling, cc. of tetrahydrofuran, containing 5 mol. equiv. of methyl magnesium bromide.

The mixture was stirred for 2 hours at 28 C., then poured into ice-water, containing dilute hydrochloric acid. The product was extracted with methylene chloride, the extract washed to neutral with water and dried over anhydrous sodium sulfate. Evaporation of the solvent at reduced pressure gave a residue, which was purified by crystallization from methylene chloride-hexane to afford 16a-methyl5a,6p-dichloro-l9-nor-pregnan-3fi-ol-20-one.

The latter compound was treated with chromous chloride solution, as described in Preparation 2, thus giving 16u-methyl-l9-nor-A -pregnen-3pol-20pne, which upon conventional acetylation in pyridine atforded the corresponding S-a-cetate.

The latter compound, was treated in accordance with Preparation 3, thus giving successively:

16e-m-ethyl-l9-nor-A -pregnadiene-3 S,20fl-diol diacetate,

160: methyl 5a,6u;17a,20e-bis-oxido 19-nor-pregnane- 35,20/8-diol diacetate,

l6a methy'l-5 6a-oxido-l9-nor-pregnane-3 3,17a-diol- 20-one-3-acetate,

1 6a-methyll9-nor-A pregnene-3 p, 17 u-diol-ZO-one- 3-acetate,

16m-methyl-1 9-nor-A -pregnene-3 3, l7u-diol-20-onediacetate,

l 6a-niethyl-17a-acetoxy-19-nor-A -pregnen-3B-ol-20-one,

16ot-H1CthY1-17 a-acetoxy-19-nor-A -pregnen-3,20-dione and 4, l 6 :x-dimethyl- 17 a-iacetoxyl9-nor-A -pregnen-3,20-dione.

PREPARATION 5 A cooled solution of 4 g. of 4,l6a-dimethyl-l7a-acetoxy-19-nor-A -pregnene-3,20-dione in 30 cc. of tetrahydrofu-ran and 18 cc. of methanol was treated under continuous stirring with 6 g. of pure calcium oxide, in small portions, and then with 6 g. of iodine. 'I he stirring was continued at room temperature until the solution turned pale yellow, The mixture was poured into ice water containing 18 cc. of acetic acid and 2 g. of sodium thiosul-fate. After stirring for 15 minutes the solution was decanted and the precipitate was collected by filtration, thus giving 4,16m-dimethyl-21-iodo17a-acetoxy-19-nor-A p-regnene-3,20-dione. The crude product was dried in vacuum, dissolved in 20 cc. of acetonitrile and treated drop'wise with 1.4 g. of silver fluoride dissolved in 3 cc. of water. After a short time, silver iodide started to separate leaving the 21-fl:uoro-pregnan derivative in solu tion. The mixture was kept for 24 'hours at room temperature and filtered. Concentration of the filtrate under vacuum gave a crude product which after crystallization from methanol-acetone yielded 4,16u-dimethyl-21-fluoro 17a.-acetoxy-19-nor-A -pregnene-3,20-dione.

Following the same procedures, 4-methyl-16a,17a-iso propylidendioxy l9 nor A -pregnene-3,20-'dione and 4- methyl 17a-acetoxy-l9-nor-A -pregnene-3,20-dione were converted first into the corresponding 2l-iodo derivatives and thereafter respectively into: 4-met'hy1-21-fluorol6a,17z isopropy-lidendioxy 19- n0r-A wpregnene-3,20- dione and 4-methyl-21-fiuoro-17a-acetoxy-19-n'or-A -pregnene-3,20-dione.

Example I A solution of 2 g. of sodium horohydride in 30 cc. of methanol was added with stirring to a solution of 2 .g. of 4-niethyl progesterone in 40 cc. of tetnahydrofuran. The mixture was kept at room temperature overnight, the excess reagent was decomposed by addition of acetic acid, the resulting solution concentrated to small volume in vacuo and diluted with water. The product was extracted with ethyl acetate, the extract washed with water, dried and evaporated. Crystallization of the solid rrom acetonehexane gave a mixture of 4-methyl-A pregnene-3@2018- diol and the Six-isomer thereof.

1 g. of the above mixture was heated on the steam bath with cc. of 50% acetic acid under nitrogen for 1 hour, it was then concentrated under vacuum to a small volume and poured into water. The precipitate was collected, washed well with water, dried and recrystallized from acetone-hexane, thus furnishing 4-methyl-A -pregnadien- 205-01.

The star-ting compounds listed below, were treated following the above techniques, thus giving first a mixture of the corresponding 3,8,20/8-diols and 3a-isomers thereof and thereafter the respective products disclosed hereinafter. a

A solution of 6 g. of 4-methyl-A -pregnadien-20fl-ol obtained according to Example 1, in 120 cc. of pyridine was added to a mixture of 6 g. of chromic trioxide in 120 cc. of pyridine. The reaction mixture was kept at room temperature overnight. It was then diluted with ethyl acetate, filtered through celite and the filtrate washed well with water, dried and evaporated to dryness. Crystallization from acetone-hexane afforded 4-methyl-A pregn-adien-ZO-one.

Following the above method there were treated the starting compounds listed below, thus yielding the corresponding products hereinafter set forth.

Starting Compounds Products 4-methy119-nor-A -pregnadicn- 4-methy1-19-nor-A -pregnadlenone. 4,160:-dimethyl-17wacetoxy-A pregnadien-20-one. 4-methyl-21-fiuoro-17a-acetoxy- A -pregnadien-2O-one. 4-methyl-A -pregnadienerlfia,

17a-diol-20-one-16,17-acetonide. 4-methyl-A -=-pregnadieno-16a,

Uta-1di01-20-one-16,17-acetophcnon e.

4,lopi-dirnethylh -pregnadlen- 4-methyl-A -pregnadiene-16a,

17a, 20fl-trlol-l6,17-acetonide.

t-methyl-n -pregnadiene-16a, 17a,20B-triol-16,17-acetophenonide.

Example III A solution of 0.17 g. of potassium hydroxide in 0.2 cc. of water and 2.5 cc. of methanol was added over 30 minutes to a boiling solution of 1 g. of 4-methyl-l7aacetoxy-A -pregnadien-20-one, in 30 cc. of methanol under an atmosphere of nitrogen. Boiling was continued for a further 2 hours and the solution was then cooled, neutralized with acetic acid and concentrated under reduced pressure. Addition of water, followed by crystallization of the precipitated solid from acetone-hexane, produced 4-methyl-A -pregnadi6i1-17a-ol-20-one.

Following the same technique there were treated 4,16udimethyl 17a acetoxy A pregnadien 20 one and 4 methyl 21 fluoro 17o: acetoxy A pregnadien 20-one, thus affording correspondingly: 4,16a-dimethyl- A -pregnadien-17a-ol-20-one and 4-methyl-21-fluoro- A -pregnadien-17a-0l-20-one.

Example IV To a solution of 5 g. of 4-methyl-A -pregnadien-17w ol-20-one in 100 cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonic acid and cc. of propionic anhydride and the mixture was allowed to stand -for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to efiect hydrolysis of the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from ether-hexane produced 4-methyl-A -pregnadicn-l7a-ol-20-one-propionate.

Following the same technique there were treated 4,16- dimethyl-A -pregnadien-l7a-ol-20-one and 4-methyl-2lfluoro-A -pregnadien-17a-ol-20-one, thus affording correspondingly 4,16a-dimethyl A pregnadien-17a-ol-20- one-propionate and 4-methyl 21 fluoro-A fi-pregnadienl7u-ol-20-one-propiona-te.

Example V Following the foregoing procedure, but substituting propionic anhydride by caproic anhydride, there were obtained 4-methyl-A pregnadien-l17a-ol-2-0-one caproate, 3,l6a-dimethyl-A pregnadien-17a-ol-20-one caproate, and 4-methyl-2l-fluoro'A -pregnadien-17ol-20-one caproate.

Example VI 1 g. of 4-methyl-A -pregnadiene-l6a,l7a-diol-2O one- 16,17-acetonide was heated on the steam bath with 20 cc. of 60% formic acid for 1 hour, cooled, diluted with water and the precipitate was collected, washed with water, dried, and recrystallized from acetone-hexane, thus affording 4-methyl-A -pregnadiene-16a,l7a-diol-20 one.

Example VII The preceding compound was treated following the procedure described in Example 4, thus giving 4-methyl- A -pregnadiene-l6a,17a-diol-20-one-l6,l7-dipropionate.

Example VIII Example IX A mixture of 1 g. of the foregoing monoester 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave 4-methyl-A pregnadiene 1602,1700 diol 20 one l6 acetate l7 propionate.

Example X A mixture of 1 g. of 4-methyl-A -pregnadiene-16a,17a diol-ZO-one; 4 cc. of pyridine and 2 cc. of caproic anhydride was kept at room temperature Overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave 4-methyl-A -pregnadiene-16a,l7oc-diol-20-onel 6-caproate.

Example XI 4-16 dimethyl 17oz acetoxy 19 nor A pregnene-3,20-dione was successively treated in accordance with Examples I and H, thus respectively yielding 4,16- dimethyl-17a-acetoxy-19-nor-A epregnadien-2OB-ol and 4,160: dimethyl 17cc acetoxy 19 nor A pregnadien-ZO-one.

Example XII 4 methyl 16ot,l7a isopropylidendioxy 19 nor A -pregnene-3,20-dione was consecutively treated according to Examples I and H, furnishing respectively, 4-methyl 16a,17a isopropylidendioxy l9 nor 13 pregnadien-ZOfi-ol and 4-methyl-16a,17a-isopropylidendioxy-19- nor-A -pregnadien-20-one.

Example XIII 4 methyl 17o: acetoxy 19 nor A pregnene 3,20-dione was treated following successively the proccdures described in Examples I and II, thus giving respectively 4-methyl-17at-acetoxy-l9-nor-A pregnadien 2018-01 and 4-methyl-17a-acetoxy-19-nor-A -pregnadien- 20-one.

Example XIV 4,160: dimethyl 21 fluoro 17a acetoxy 19 nor A -pregnene-3,20-dione was successively treated in accordance with Example I and 11, thus giving correspondingly 4,160: dimethyl 21 fluoro 17a acetoxy 19 nor A -pregnadien-20p-o1 and 4,16a-dimethyl-Z1- fluoro-17aacetoxy-19-nor-A -pregnadien-2-0-one.

Example XV 4 methyl 21 fiuoro 16,17u isopropylidendioxy 19-nor-A -pregnene-3,ZO-dione was successively treated according to Examples I and H, thus furnishing respectively: 4-methyl-21-fluoro-16a,l7a-isopropylidendioxy-l9- nor-A -pregnadien-20/3-ol and 4-methyl-2l-fluoro-16u, 17a-isopropylidendioxy-l9-nor-A -pregnadien-ZO-one.

Example XVI 4 methyl 21 fluoro 17oz acetoxy 19 nor A pregnene-3,20-dione was treated following successively the procedures described in Examples I and II, thus producing respectively 4-methyl-21-fluoro-17u-acetoxy-19-nor-A pregnadien-ZOB-ol and 4-methyl-2l-fluoro-17a-acetoxy- 19-nor-A -pregnadien-20-one.

Example XVII 4,160: dimethyl 17oz acetoxy 19 nor A pregnadien-ZO-one, 4,16a-dimethyl-21-fluoro-17a-acetoxy-19- nor-A -pregnadien-20-one, 4-methyl-21-fiuoro-17a-acetoxy-19-nor-A -pregnadien-20-one and 4-methyl-17aacetoxy-19-nor-A -pregnadien-20-one were treated in accordance with Example III, yielding respectively: 4,167;- dimethyl-l9-nor-A -pregnadien-17a-ol-20-one, 4,16a-dimethyl 21 fiuoro 19 nor A pregnadien 17a ol-24-one, 4-methyl-21-fluoro-19-nor-A -pregnadien17aol-20-one, and 4-methyl-19-nor-A -pregnadiem17a-ol- 20-one.

Example XVIII 4 methyl 21 tfiuoro 16a,17u isopropylidendioxy 19-nor-A -pregnadien-20-one and 4-methyl16a,17a-is& propylidendioxy 19 nor A pregnadien-ZO-one were treated following the procedure described in Example VI thus afiording respectively 4-methyl-21-fluoro-l9-nor- A -pregnadiene-l6a,17u-diol-20-one and 4-methyl-19- nor-A pregnadiene-16a,17a-dio120-one.

We claim:

1. A compound of the following formula:

Ego m wherein Y is selected from the group consisting of hydrogen and fluorine; R is a member of the group consisting of hydrogen and methyl; R is selected from the group consisting of hydroxyl and a hydrocarbon car-boxylic acyloxy group of less than 12 carbon atoms; R is a member of the group consisting of hydrogen, a-methyl, ,8- methyl, a-hydroxyl and an wt-hydrocarbon car-boxylic acyloxy group of less than 12 carbon atoms, R and R together are in addition the group wherein P is a lower alkyl group and Q is selected from the group consisting of a lower alkyl, an aryl and an aralkyl group, each containing up to 8 carbon atoms.

. 4-methyl-A -pregnadien-2O-one.

. 4methyl-19-nor-A -pregnadien-ZO-one.

. 4-methy1-17a-acetoxy-A -pregnadien-20-one.

. 4,16a-dimethyl-A -pregnadien-20-one.

. 4,16 3-dirnethyl-A -pregnadien-20-one.

. 4,16a-dimethyl-17a-acetoxy-A -pregnadien-20-one.

. 4 methyl-21-fiuoro-17u-acetoxy-A -pregnadien-20- 

1. A COMPOUND OF THE FOLLOWING FORMULA: 